Congress Sponsors Search Write About màj : 17/06/99

previous  next Provided by/avec le support de :     S-221 87     Lund Sweden ARLS information : Myrna Mansson Get the paper version from your local Marketing representative. Find the address ont the net at http://www.astrazeneca.com/Marketing-worldwide N°2   1998 AstraZeneca Respiratory Literature Service (see other Expert comments on Asmanet or N°1 1998) For many years, AstraZeneca Draco laboratories have brought to the asthmolgist community an excellent "Respiratory Literature Service" (ARLS) with an alert to new references, selected summaries and comments by a group of experts. In 1997, AstraZeneca is extending this concrete service with Asmanet in order to take advantage of the Internet capabilities. The following comments have been edited ( HTML format) to smooth the reading with hypertext links to integrate the comment in the Asmanet server and the worldwide distributed library on asthma, such as : abstract of the commented paper, references as seen on Medline and others, author's e-mail ...   Title Authors Journal Reviewer 1 The safety of asthma and allergy in medications during pregnancy Schatz M, Zeiger RS, Harden K, et al. J Allergy and Clin Immunol 1997;100:301-306. Professor Duncan Geddes 2 Effect of inhaled formoterol and budesonide on exacerbations of asthma Pauwels RA, Löfdahl C-G, Postma DS, et al. N Engl J Med 1997;337: 1405-1411 Professor Duncan Geddes 3 A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma Evans DJ, Taylor DA, Zetterström O, et al N Engl J Med 1997;337: 1412-1418 Professor Duncan Geddes 4 A comparison between emergency diagnostic and treatment unit (EDTU) and inpatient care in the management of acute asthma McDermott MF, Murphy DG, Zalenski RJ, et al. Arch Intern Med 1997;157: 2055-2062 Professor Philippe Godard 5 Association between b 2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics Tan S, Hall IP, Dewar J, et al. Lancet 1997;350: 995-999 Professor Philippe Godard 6 Effect of inhaled formoterol and budesonide on exacerbations of asthma Pauwels RA, Löfdahl C-G, Postma DS, et al. N Engl J of Med 1997;337: 1405-1411. Professor Philippe Godard 7 Effect of inhaled formoterol and budesonide on exacerbations of asthma Pauwels RA, Löfdahl C-G, Postma DS, et al. N Engl Journal of Medicine 1997;337: 1405-1411 Ass. Professor Leif Rosenhall 8 Comparative lung delivery of salbutamol given via Turbuhaler and Diskus dry powder inhaler devices Lipworth BJ, Clark DJ. Eur J Clin Pharm 1997;53:47-49 Ass. Professor Leif Rosenhall 9 Effect of inhaled formoterol and budesonide on exacerbations of asthma Pauwels RA, Löfdahl C-G, Postma DS, et al. N Engl Journal of Medicine 1997;337: 1405-1411 Professor John H. Toogood 10 Esophageal candidiasis as a complication of inhaled corticosteroids Simon MR, Houser WL, Smith KA, Long PM. Ann Allergy Asthma Immunol 1997;79:333-338 Professor John H. Toogood AstraZeneca Draco laboratories is also supporting the European Federation of Asthma and Allergy Associations which can be seen at http://www.efanet.org/ Access for abstracts to Medline through Healthgate (http://www.healthgate.com/HealthGate/MEDLINE/search.shtml ) or through HealthWorld Medline Search (http://www.healthy.net/library/search/medline.htm ): direct access to the abstract whenever it's available is not possible. You have to perform a "search" using the search engine (and be exposed to the local advertiser banner which sort-of pays for the free access). You will then go through the following steps : Select the names of the first two authors (or part of the title) and do a "copy" (ctrl C on a PC under Windows) so that you will have the search key at hand. Click on the link in order to get the HealthGate/HealthWorld search home page. Paste the search key (ctrl V) into the search window displayed on your screen and perform the search. The search engine will send you back the list of papers with those two authors. HealthWorld search engine will give you related papers if you select it by the title. You will then select the link which you want if the paper is known and click on the link to get the abstract. ...

Asthma and allergy are amongst the most common medical problems to complicate pregnancy and so the safety of commonly used asthma treatments is a major concern among patients and their doctors. Although there have been no suggestions that such treatments are harmful, systematic evidence is lacking.

The study by Schatz et al assessed the safety of asthma medications, antihistamines and decongestants prespectively in 824 pregnant women with and 678 pregnant women without asthma.

There was no increase in perinatal risk, in association with commonly used asthma and allergic medications. The only significant finding was an increase in pre-eclampsia (odds ratio = 2.0) in association with oral corticosteroid use.

This study provides useful reassurance for pregnant patients and doctors alike.

Title (1): . The safety of asthma and allergy in medications during pregnancy (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Schatz M; Zeiger RS; Harden K; Hoffman CC; Chilingar L; Petitti D
Address : Department of Allergy' Kaiser-Permanente Medical Center' San Diego' CA 92111' USA.
Source : J Allergy Clin Immunol, 100(3):301-6 1997 Sep
Abstract :
BACKGROUND: Although no asthma or allergy medications can be considered proven safe for use during pregnancy' these medications are often used to prevent the potential direct and indirect consequences of uncontrolled asthma or allergy. OBJECTIVE: The safety of asthma medications' antihistamines' and decongestants was assessed in a prospectively monitored cohort of 824 pregnant women with and 678 pregnant women without asthma. METHODS: Medications used since conception were recorded on each subJect`s initial visit (< 28 weeks` gestation). Thereafter' diary cards for medications were completed by the patient through the time of delivery. Perinatal outcomes were compared in exposed versus unexposed individuals. A multivariate analysis accounted for the potential effects of age' parity' smoking' race' weight gain during pregnancy' maternal pulmonary function' acute asthmatic episodes' and multiple medication exposure. RESULTS: No significant relationships were identified between maJor congenital malformations and first trimester or any exposure to beta-agonists' theophylline' cromolyn' corticosteroids' antihistamines' or decongestants. In the multivariate analyses' oral corticosteroids were independently associated with preeclampsia (odds ratio = 2.0' p = 0.027)' but no other independent associations were observed between asthma or allergy medications and adverse perinatal outcomes. CONCLUSION: Use of most common asthma and allergy medications during pregnancy was not associated with increased perinatal risks.

... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm

The study by Pauwels et al is a further large study examining the contribution to asthma control of inhaled corticosteroids and long-acting b ₂-agonists. In the study 852 patients were randomised. Therefore, the size of the groups were large enough to make the results both reliable and interesting. The study allows the following conclusions:

• There were no important adverse effects or loss of control of asthma associated with long-term use of formoterol.
• In terms of symptom control and lung function, the addition of formoterol to budesonide was better than increasing the dose of budesonide.
• In terms of controlling mild exacerbations of asthma, the addition of formoterol was superior to increasing the dose of budesonide.
• In terms of preventing severe exacerbations of asthma, increasing the dose of budesonide was better than the additional formoterol.
• A dose of 200 m g budesonide provided the majority of the benefit. It seems that only the subgroup of patients with frequent severe attacks of asthma benefit more from an increase in the dose of budesonide while the other groups benefit more from the addition of formoterol.

Overall the study is valuable and helps to define the best approach to treating different patient groups.

The study is also interesting in mechanistic terms, suggesting that in recent years the importance of inflammation has been overstated while the importance of treating bronchospasm has been understated.

Title (2) : Effect of inhaled formoterol and budesonide on exacerbations of asthma (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Pauwels RA; L ofdahl CG; Postma DS; Tattersfield AE; O`Byrne P; Barnes PJ; Ullman A
Address : Department of Respiratory Diseases' University Hospital' Ghent' Belgium.
Source :N Engl J Med, 337(20):1405-11 1997 Nov 13
Abstract :
BACKGROUND: The role of long-acting' inhaled beta2-agonists in treating asthma is uncertain. In a double-blind study' we evaluated the effects of adding inhaled formoterol to both lower and higher doses of the inhaled glucocorticoid budesonide. METHODS: After a four-week run-in period of treatment with budesonide (800 microg twice daily)' 852 patients being treated with glucocorticoids were randomly assigned to one of four treatments given twice daily by means of a dry-powder inhaler (Turbuhaler): 100 microg of budesonide plus placebo' 100 microg of budesonide plus 12 microg of formoterol' 400 microg of budesonide plus placebo' or 400 microg of budesonide plus 12 microg of formoterol. Terbutaline was permitted as needed. Treatment continued for one year; we compared the frequency of exacerbations of asthma' symptoms' and lung function in the four groups. A severe exacerbation was defined by the need for oral glucocorticoids or a decrease in the peak flow to more than 30 percent below the base-line value on two consecutive days. RESULTS: The rates of severe and mild exacerbations were reduced by 26 percent and 40 percent' respectively' when formoterol was added to the lower dose of budesonide. The higher dose of budesonide alone reduced the rates of severe and mild exacerbations by 49 percent and 37 percent' respectively. Patients treated with formoterol and the higher dose of budesonide had the greatest reductions -- 63 percent and 62 percent' respectively. Symptoms of asthma and lung function improved with both formoterol and the higher dose of budesonide' but the improvements with formoterol were greater....

... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm

This is a further useful study examining the interactions between well established asthma treatments. 62 patients with poorly controlled asthma were randomised to receive either 400 m g of inhaled budesonide with 250-375 mg theophylline or 800 m g of inhaled budesonide. When compared with the run-in period (inhaled budesonide 400 m g alone) both groups showed an improvement in lung function of between 3 and 5 per cent. Improvements in the spirometric measurements were slightly greater in the theophylline group, while peak flow changes were the same.

This study provides data confirming that bronchodilators as well as anti-inflammatory treatment are useful in the treatment of asthma. However, some remarks can be made:

• - The authors seemed reluctant to compare their study with those of a similar design using salmeterol or formoterol although superficial comparisons suggest that the inhaled long-acting bronchodilators performed better than theophylline.
• - There were no data in this study to suggest that theophylline was working as an immuno-modulator rather than a bronchodilator.
• - The doses of theophylline used were relatively low and achieved a median serum level of 8.7 m g per ml. Unfortunately it was not clear whether the improvements in the theophylline treated group were related to the serum level or not. In spite of these low levels, headache and gastrointestinal disturbance occurred in 25% of the theophylline treated group.

In conclusion, long-acting bronchodilators are an effective adjunct to inhaled corticosteroids.

Now, a cost-benefit analysis comparing theophylline with long-acting inhaledb -agonists remains an important priority.

Title (3): . A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Evans DJ; Taylor DA; Zetterstrom O; Chung KF; O`Connor BJ; Barnes PJ
Address : Department of Thoracic Medicine' National Heart and Lung Institute' Imperial College School of Medicine' London' United Kingdom.
Source : N Engl J Med, 337(20):1412-8 1997 Nov 13
Abstract :
BACKGROUND: Inhaled glucosteroids and oral theophylline are widely used to treat asthma. We compared the benefits of adding theophylline to inhaled glucosteroid with those of doubling the dose of inhaled glucosteroid in patients with persistent symptoms despite the use of inhaled glucosteroid.
METHODS: In a double-blind' placebo-controlled trial' we randomly assigned 62 patients to receive either 400 microg of inhaled budesonide (low-dose budesonide) with 250 or 375 mg of theophylline (depending on body weight) or 800 microg of inhaled budesonide (high-dose budesonide). All doses were given twice daily for three months. Lung function was measured serially' and patients kept records of peak expiratory flow' symptoms' and albuterol use. The effects of treatment on endogenous cortisol levels were also assessed. RESULTS: Both treatments resulted in improvements in lung function that were sustained throughout the study. As compared with treatment with high-dose budesonide' treatment with low-dose budesonide plus theophylline resulted in greater improvements in forced vital capacity (P=0.03) and forced expiratory volume in one second (P= 0.03). There were significant and similar reductions in beta2-agonist use and the variability of peak expiratory flow' a correlate of bronchial hyperresponsiveness and the severity of asthma. Serum cortisol concentrations were significantly reduced in the group given high-dose budesonide (from a mean [+/-SE of 18.4+/-2.4 microg per deciliter to 15.9+/-2.1 microg per deciliter' P=0.02) but were unchanged in the other group. The median serum theophylline concentration was 8.7 microg per milliliter (therapeutic range' 10 to 20) among those who received theophylline. Bothtreatments were well tolerated. CONCLUSIONS: For patients with moderate asthma and persistent symptoms' low-dose inhaled budesonide with theophylline and high-dose inhaled budesonide producedsimilar benefits....

... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm

Although the management of acute exacerbations of asthma is not one of the major problems, the number of papers which deal with it is still high.

McDermott et al. studied patients with acute asthma who failed to meet discharge criteria after 3 hours of treatment with inhaled adrenergic agonists and steroids in an EDTU (emergency diagnostic and treatment unit). They compared the effect of further treatment at the EDTU with routine therapy in a hospital ward.

They demonstrated that an additional stay of 9 hours in the EDTU was beneficial: 59% of the patients were discharged home. In other words, additional treatment in the EDTU prevented hospitalisation. Moreover, it was shown that this treatment improved the satisfaction and the quality of life of the patients, and saved money.

The authors explained that additional EDTU treatment is useful because the maximal effect of corticosteroids is obtained after at least 6 hours.

The study was well designed and conducted. The results are presented in six tables and two figures. The authors found support for additional EDTU treatment.

However, some remarks can be made:

• The study was conducted in young adults (18-55 years) who had a less than 10 pack-per-year history of smoking. However, it has been demonstrated that older asthmatics, who smoke are especially at risk of relapse and dying (Ch. H. Marguette - An J Resp Crit Care Med).
• Theophylline was used as discharge medication. The dose was adapted on the basis of blood assessment and was not performed on a regular basis. (?)
• Treatment at discharge is not fully explained, for example, the dose of inhaled steroids has not been indicated.
• In both groups, the probability of patients remaining relapse free decreased quite rapidly with time. Probably, this indicates that the patients were not adequately controlled.

In conclusion, chest physicians must send a clear message: acute asthmatic patients discharging from hospital or EDTU need a careful follow-up treatment.

Title (4): . A comparison between emergency diagnostic and treatment unit (EDTU) and inpatient care in the management of acute asthma (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : McDermott MF; Murphy DG; Zalenski RJ; Rydman RJ; McCarren M; Marder D; Jovanovic B; Kaur K; Roberts RR; Isola M; Mensah E; RaJendran R; Kampe L
Address : Department of Emergency Medicine' Cook County Hospital' Chicago' IL' USA.
Source : Arch Intern Med, 157(18):2055-62 1997 Oct 13
Abstract :
BACKGROUND: Emergency diagnostic and treatment units (EDTUs) may provide an alternative to hospitalization for patients with reversible diseases' such as asthma' who fail to adequately respond to emergency department therapy. OBJECTIVE: To evaluate the medical and cost-effectiveness' patient satisfaction' and quality of life of patients receiving EDTU care for acute asthma compared with inpatient care. METHODS: A prospective' randomized clinical trial performed at 2 urban public hospitals enrolled patients with acute asthma (age range' 18-55 years) not meeting discharge criteria after 3 hours of emergency department therapy. Patients were treated with inhaled adrenergic agonists and steroids in an EDTU for up to 9 hours after randomization or with routine therapy in a hospital ward. Patients were followed up for 8 weeks. MAIN OUTCOME MEASURES: Discharge rate from the EDTU' length of stay' relapse rates' days missed from work or school' days incapacitated during waking hours' symptom-free days and nights' nocturnal awakenings' direct medical costs' patients satisfaction' and patient quality of life. RESULTS: The study consisted of 222 patients with asthma. Sixty-five patients (59%) treated in an EDTU were discharged home; the remainder were admitted to the hospital. There were no differences during the follow-up period in relapse rates (P = .74) or in any other morbidities between the EDTU and inpatient groups. There were significant differences in the length of stay' patient satisfaction' and quality of life favoring EDTU care. The mean (+/-SD) cost per patient in the EDTU group was $1202.79 +/- $1343.96' compared with $2247.32 +/- $1110.18 for the control group (P < .001)....

... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm

In current research institutes, intensive discussion is going on about the possible deleterious effect of regularly used b ₂-agonists. These effects might range from tachyphylaxis (a lack of effect) to death. In addition, some studies suggested that regular use of b ₂-agonists is accompanied by a gradual decline in FEV₁. Whether these results modified clinical practice is unknown. Nevertheless, some years ago regular use of long-acting b ₂-agonists was introduced and most patients appear to benefit from them.

Deleterious effects by b ₂-agonists might be caused by b ₂-receptor desensitisation. Therefore, Tan et al. studied whether b ₂-adrenoceptor polymorphism is linked to b ₂ desensitisation.

The results "suggested" (as stated by the authors) that there may be a subset of individuals in whom bronchodilator desensitisation occurs when long-acting b ₂-agonists are used on a regular basis. In particular, the homozygous Gly-16 form of the b ₂-receptor is prone to desensitisation. Indeed, some of our patients require a regular boost of oral corticosteroids. The decision to add oral corticosteroids is made on an empirical (clinical!) basis but, maybe, this could be predicted by knowing if patients were homozygous Gly16.

In general, the relation between b ₂-adrenoceptor polymorphyism and an abnormality is especially exiting in the field of predictive medicine. It would be interesting to know in advance which patient will respond to a specific drug.

In the near future, many other asthmatic phenotypes might be explained by genotipic abnormalities. Such a development will be very exiting. However, still clinical evaluation will be the mainstay of good science leading to improved asthma management.

Title (5): . Association between b 2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Tan S; Hall IP; Dewar J; Dow E; Lipworth B
Address : Department of Clinical Pharmacology and Therapeutics' University of Dundee' Ninewells Hospital and Medical School' UK.
Source : Lancet, 350(9083):995-9 1997 Oct 4
Abstract :
BACKGROUND: In-vitro studies have suggested that polymorphisms of the beta 2-adrenoceptor may influence the desensitisation induced by beta 2-agonists. We investigated the influence of beta 2-AR polymorphism on the development of bronchodilator desensitisation in asthma patients. METHODS: We carried out an analysis of 22 moderately severe stable asthmatics' mean age 38 years' FEV1 63% of predicted and FEF25-75 38% of predicted' who received a median inhaled corticosteroid dose of 1000 micrograms/day. Patients were randomly assigned inhaled placebo or inhaled formoterol 24 micrograms bid for 4 weeks each in a crossover study. Bronchodilator dose-response curves were made at the end of each treatment period by use of cumulative doses of formoterol (6-108 micrograms) with FEV1 and FEF25-75 measured 30 min after each dose' and up to 6 h after the last dose. We calculated the degree of bronchodilator desensitisation by comparing the dose-response (for maximum and 6 h) after placebo with that after formoterol' and expressed this degree as a percentage of placebo response. Patients were divided into groups according to genotype at codon 16: homozygous Arg 16 (n = 4)' heterozygous Arg 16/Gly 16 (n = 8)' and homozygous Gly 16 (n = 10). At codon 27: homozygous Gln 27 (n = 5)' heterozygous Gln 27/Glu 27 (n = 11)' and homozygous Glu 27 (n = 6). FINDINGS: We found a significantly (p < 0.05) greater degree of bronchodilator desensitisation with homozygous Gly 16 than with homozygous Arg 16 for maximal FEV1 response: -8% (Arg 16) vs 46% (Gly 16); and for maximal FEF25-75 response: -32% (Arg 16) vs 74% (Gly 16; 95% CI 15-92% and 49-164%' respectively)....

... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm

The aim of the study by Pauwels et al. was to demonstrate, that adding a long acting b ₂-agonists to low or high dose of inhaled corticosteroids not only improves lung function and symptoms, but also does not induce any loss of asthma control.

The rate of exacerbation was the primary outcome. It is interesting to read the definition of severe and mild exacerbations in the publication:

"A severe exacerbation was defined as one requiring treatment with oral glucocorticoids, as judged by the investigator, or a decrease in the preak expiratory flow as measured in the morning to more than 30 percent below the base-line value on two consecutive days."

"Mild exacerbations were defined as days when one of the following occurred: a peak expiratory flow in the morning that was more than 20 percent below the base-line value; the use of more than three additional inhalations of terbutaline per 24 hours as compared with the base-line period; or awakening at night due to asthma. Single, isolated days of mild exacerbations were not counted."

At the moment no consensus exists on how to define exacerbation rates. Therefore, large discrepancies occur among clinical studies with regard to assessing exacerbations..

In addition to exacerbation rates, several other clinical outcomes were measured such as episode free days, symptom scores, rescue medications and awakenings. The results of these outcomes have been summarised in table 2 (p. 1408 of the publication). The table is an excellent aid to understanding how the patients improved in each group.

Some comments can be made viewing the table with clinical outcomes:

• In the group treated with high dose budesonide plus formoterol the rate of severe exacerbations was 0.34/patient/year and in the group treated with low dose budesonide the rate of exacerbations was 0.91/patient/year. An exacerbation rate of 0.91 might be regarded as acceptable and not clinically different from 0.34.
• For each clinical outcome, it might be questioned whether the differences between the groups are really clinically different.
• Taking into account all clinical outcomes, the best overall result is observed in the group that was treated with a high dose budesonide plus formoterol. Comparing the different groups clearly shows a kind of dose response relationship.

In other words, asthma is not only PEFR and/or FEV₁ but should be analysed by all its clinical phenomena. A table such as table 2 in the publication could be used on a daily basis to help the clinician discussing asthma with his patient and choosing the right treatment.

In addition, the results shown in the table with clinical outcomes indicate that about 80% of the patients who received formoterol plus a high dose of inhaled steroids were free of severe exacerbations. This means that 20% had severe exacerbations. Therefore, additional treatment or alternative strategy should be considered in more severe patients.

Title (6): . Effect of inhaled formoterol and budesonide on exacerbations of asthma (partial abstract from http://www.healthy.net/library/search/medline.htm )

see "Title 2"

... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm

The study by Pauwels et al. is an important, large, well planned, conclusive and "expensive" study. It will be quoted in many situations and it will be discussed among everyone interested in asthma.

The study clearly demonstrates that addition of long-acting, inhaled b ₂-agonists (formoterol) is superior to increasing the dose of inhaled steroids in improving symptoms and lung function in patients not well controlled on a low or medium dose of inhaled steroids.

From a clinicians point of view, the results are by no means spectacular. Since the introduction of long-acting b ₂-agonists we know that they are of great value for unstable asthmatics. They have a prophylactic and stabilising effect which cannot be achieved with oral steroids.

When asthma symptoms are inhibited, the inflammatory process, of course, is also diminished. Therefore, the b ₂-agonist in its prophylactic action has anti-inflammatory effects. This explains the important beneficial effects. Corticosteroids do not have the same protective effects as b ₂-agonists. This is illustrated by the fact that before a histamine provocation test the use of b ₂-agonists must be stopped while this is not necessary with steroids.

Overall, the Formoterol And Corticosteroids Establishing Therapy (FACET) study by Pauwels et al is very important and useful.

Title (7): . Effect of inhaled formoterol and budesonide on exacerbations of asthma (partial abstract below from http://www.healthy.net/library/search/medline.htm )

see "Title 2"

... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm

To be successful, inhalation therapy needs a good inhaler device! Therefore, it is important that different devices are carefully compared and evaluated.

The study by Lipworth and Clark is a proper comparison between Turbuhaler and Diskus examined in healthy subjects. In 6 minutes, either 6 doses of 0.2 mg salbutamol with Diskus or 12 doses of 0.1 mg salbutamol with Turbuhaler were inhaled.

The results indicate that Turbuhaler delivers a larger dose of salbutamol than Diskus. This was concluded by comparing the salbutamol plasma concentrations and heart rates.

The main objection is, of course, that the different numbers of inhalations may explain part of the difference.

The authors also stress that the result cannot be transferred to other drugs (e.g. steroids) or to patients with reduced lung function.

Overall, the study by Lipworth and Clark is a good study. These types of direct comparisons between inhaler devices are necessary and important to perform.

Title (8): . Comparative lung delivery of salbutamol given via Turbuhaler and Diskus dry powder inhaler devices (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Lipworth BJ; Clark DJ
Address : Department of Clinical Pharmacology' Ninewells Hospital & Medical School' University of Dundee Scotland.
Source : Eur J Clin Pharmacol, 53(1):47-9 1997
Abstract :
OBJECTIVE: The environmental concerns surrounding the use of chlorofluorocarbons (CFC) have led to a resurgence of interest in dry powder inhaler devices. The aim of our study was to compare two commonly used dry powder inhaler devices' namely the Turbuhaler and Diskus. METHODS: Eight healthy volunteers with a mean (SEM) age of 21 years (0.8) were studied using a randomised single-investigator blind crossover design. Single doses of 1.2 mg salbutamol as Turbuhaler (12 x 100 micrograms) and Diskus (6 x 200 micrograms) were administered over 6 min. Mouth rinsing was performed after every inhalation. Lung delivery from each device was assessed by measuring the early plasma salbutamol profile at 5' 10' 15 and 20 min after inhalation. RESULTS: Significant differences in lung delivery were found between the Diskus and the Turbuhaler for salbutamol Cmax 3.21 vs 4.04 ng.ml-1' respectively and Cav 2.65 vs 3.73 ng.ml-1' respectively. This amounted to a 1.28-fold difference (95% CI 1.09 to 1.45) between these devices for Cmax and a 1.42-fold difference (95% CI 1.57 to 1.66) for Cav. CONCLUSION: We have demonstrated that' in vivo' the Turbuhaler dry powder inhaler produces significantly greater lung delivery of salbutamol than the Diskus. This illustrates that dry powder inhaler devices may have different in vivo deposition characteristics.

... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm

In patients who have poorly controlled asthma despite the application of aggressive diagnostic and environmental control measures plus the use of low dose inhaled steroid, the addition of regular salmeterol or formoterol offers an effective alternative to increasing the dose of inhaled steroid^1,2,3. The outcome of this treatment over periods longer than one year remains to be determined. The risk of allowing airways inflammation to persist unchecked, possibly leading to chronic airflow limitation, is a concern. This concern arises from the observation that, in persons with atopic asthma, inhaled salmeterol⁴ or salbutamol^{5 ,6} augment the airways smooth muscle and mast cell responses to inhaled allergen or methacholine. Furthermore, these effects cannot be prevented by concurrent inhaled steroid treatment⁷.

These considerations favour a conservative approach to the use of regular b ₂-agonist treatment as a "steroid-sparing" agent, particularly in atopic children.

References:

1. Woolcock A, Lundback B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996;153:1481-1488.

2. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol verus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 1994;344:219-224.

3. Pauwels RA, Löfdahl C-G, Postma DS, Tattersfield AE, O’Byrne P, Barnes PJ, Ullman A. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997;337:1405-1410.

4. Bhagat R, Kalra S, Swystun VA, Cockroft DW. Rapid onset of tolerance to the bronchoprotective effect of salmeterol. Chest 1995;108:1235-1239.

5. Cockroft DW, McPharland CP, Britto SA, Swystun VA, Rutherford BC. Regular inhaled salbutamol and airway responsiveness to allergen. Lancet 1993;342:833- 837.

6. Cockroft DW, O’Byrne PM, Swystun VA, Bhagat R. Regular use of inhaled albuterol and the allergen-induced late asthmatic response. J Allergy Clin Immunol 1995;96:44-49.

7. Cockroft DW, Swystun VA, Bhagat R. Interaction of inhaled b ₂ -agonist and inhaled corticosteroid on airway responsiveness to allergen and methacoline. Am J Respir Crit Care Med 1995;152:1485-1489.

Title (9): . Effect of inhaled formoterol and budesonide on exacerbations of asthma (partial abstract from http://www.healthy.net/library/search/medline.htm )

see "Title 2"

... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm

As the authors point out, esophageal candidiasis is an unusual complication of inhaled steroid treatment¹. Multiple pathogenetic codeterminants may be involved, and these may vary from patient to patient^2,3. Some codeterminants prove refractory to standard therapy. In such circumstances, a comprehensive therapeutic approach aimed at controlling all the identifiable contributing factors may be required to fully resolve the problem and prevent recurrences⁴.

References:

1. Stein MR, Shay SS, Jacobson K. Monilial eosphagitis in asthmatic patients treated with beclomethasone. J Allergy Clin Immunol 1979;63:172.
2. Hemstreet MP, Reynolds DW, Meadows J Jr. Oesophagitis - a complication of inhaled steroid therapy. Clin Allergy 1980;10:733-738.
3. Toogood JH. Complications of topical steroid therapy for asthma. Am Rev Respir Dis 1990;141:S89-S96.
4. Toogood JH. Asthma in Adults. In: Current Therapy in Allergy, Immunology and Rheumatology-3. Lichtenstein LM, Fauci AS, eds. B.C. Decker Inc., Toronto, 1988;25-31.

Title (10): . Esophageal candidiasis as a complication of inhaled corticosteroids (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Simon MR; Houser WL; Smith KA; Long PM
Address : Department of Pediatrics' Wayne State University School of Medicine' Detroit' Michigan' USA.
Source : Ann Allergy Asthma Immunol, 79(4):333-8 1997 Oct
Abstract :
BACKGROUND: Oropharyngeal candidiasis is a well-described side effect of inhaled corticosteroids. Nevertheless' few cases of esophageal candidiasis have been reported. OBJECTIVE: To present a patient with esophageal candidiasis associated with inhaled corticosteroids. METHODS: Case report. RESULTS: Our patient is a 70-year-old white woman with a 20-year history of intrinsic asthma' well controlled on triamcinolone acetonide 400 micrograms' ipratropium bromide 36 micrograms' and pirbuterol acetate 400 micrograms' each inhaled four times daily. She reported no oral steroid use for > 4 years and that she always rinsed her mouth following triamcinolone acetonide inhalation. The patient had gastritis with peptic ulcer disease in the past and developed worsening dyspeptic pain and heartburn. Following discontinuation of cimetidine and initiation of ranitidine without improvement' esophagogastroduodenoscopy was performed. Several small white patches in the mid and distal esophagus could not be removed with pressure. A biopsy confirmed the diagnosis of candidal esophagitis. Following a 4-week course of fluconazole' the patient was clinically improved and follow-up esophagogastroduodenoscopy was normal. There was no evidence of underlying cellular
immunosuppression' malignancy' or diabetes mellitus and no history of recent antibiotic usage. Delayed skin tests revealed 5 x 5 mm induration to dermatophytin. Delayed hypersensitivity to Candida and mumps tests was absent. There was strong in vitro lymphocyte transformation and a positive immediate skin test response to Candida....

... for the complete abstract, please enquire http://www.healthy.net/library/search/medline.htm

. ARLS Congrès Conçue et réalisée par: Michel Godard (at) Top
Date de création: 17 Mars 1998 - Dernière mise à jour: 17/06/99
Le secret des correspondances transmises sur le réseau Internet n'est pas garanti.
Toute personne citée dispose d'un droit d'accès, de modification, de rectification et de suppression des données le concernant (art. 34 de la loi "Informatique et Libertés" n° 78-17 du 6 janvier 1978). Pour l'éxercer adressez-vous à Michel Godard (at)